Our previous research in rats has shown that exposure to bladder inflammation during the neonatal period of development markedly enhances the degree of bladder hyperalgesia that occurs in response to a second exposure to bladder inflammation as an adult. Neonatal bladder inflammation also significantly increases micturition frequency and significantly decreases the threshold for micturition reflexes in adulthood. These outcomes are consistent with the primary symptoms of painful bladder syndrome (PBS) / interstitial cystitis (IC) and suggest that neonatal bladder inflammation may be a contributing factor to bladder disorders. The general hypothesis of the present proposal is that neonatal bladder inflammation predisposes an organism to adult bladder pain by impairing the development and/or function of an opioid inhibitory system that normally serves to suppress bladder pain. The specific hypotheses that refine and develop this general hypothesis are tested in the following specific aims: Specific Aim 1 will test the hypothesis that the estrous cycle influences the magnitude of the endogenous opioid inhibitory response evoked by bladder inflammation in the adult rat. Specific Aim 2 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by impairing a descending inhibitory system originating from neurons located in the rostroventral medulla (RVM). Specific Aim 3 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by altering <-, :- and/or 4-opioid receptor expression in the spinal cord. Specific Aim 4 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by altering spinal cord opioid peptide content. Specific Aim 5 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by reducing opioid inhibition of spinal dorsal horn neurons We believe these systematic studies, based on an innovative hypothesis, will lay the groundwork for potential novel therapeutic modalities for the treatment of urinary bladder pain by identifying opposing substrates underlying the development of bladder pain. Translation to the treatment of painful bladder syndromes would be highly probable because we will be able to identify key loci for targeted interventions. PUBLIC HEALTH RELEVANCE: We believe these systematic studies, based on an innovative hypothesis, will lay the groundwork for potential novel therapeutic modalities for the treatment of urinary bladder pain associated with painful bladder syndrome (PBS) / interstitial cystitis (IC) by identifying opposing substrates underlying the development of bladder pain. Translation to the treatment of PBS/IC would be highly probable because we will be able to identify key developmental factors that give rise to the disorders, underlying mechanisms responsible for the disorders, and loci for targeted interventions.